New safety assessment procedure for unknown NIAS

On November 15, 2013 the peer-reviewed journal Food Additives & Contaminants: Part A published an article online on “A novel safety assessment strategy for non-intentionally added substances (NIAS) in carton food contact materials” by Sander Koster and colleagues from the Netherlands Organisation for Applied Scientific Research TNO. The authors of the paper present their new Complex Mixture Safety Assessment Strategy (CoMSAS) for the evaluation of unknown non-intentionally added substances (NIAS) found in carton food contact materials (FCM). The CoMSAS facilitates the distinction between toxicologically more and less relevant substances concerning their levels of exposure and guides the focus on substances with potential health concerns. The researchers demonstrate the CoMSAS in the safety assessment of three samples of carton FCM.

Next to intentionally added substances that enhance the properties of FCM, other substances, so called NIAS, are also found in packaging materials. NIAS originate from impurities in the primary material (monomers, additives and starting substances), reaction by-products during manufacturing or decomposition processes in the final product. European legislation allows the presence of NIAS but requires a risk assessment (EU 10/2011, Art. 19 ). However, the law’s text does not specify explicit procedures for risk evaluation of NIAS, and no explicit thresholds are defined. The proposed CoMSAS intends to fill the gap involving a row of analytic screening tools. It shows the presence of both known NIAS, like mineral oil, phthalates, perfluourninated substances, etc., and unknown NIAS. In the present study, the researchers only screened for unknown NIAS. For the known NIAS they refer to the individual producers and traditional, established analytical procedures.

The decision tree-based approach of the Threshold of Toxicological Concern (TTC) is the foundation of the CoMSAS. CoMSAS can be used for the assessment of complex chemical mixtures and, according to Koster and colleagues, to “evaluate the safety of unknown NIAS present at low exposures in FCMs”. Two central advantages of this approach over other approaches were named: First, instead of the conventional detection limit of 10 µg/kg of food for substance migration, CoMSAS applies an exposure threshold of 90 µg/person/day. Furthermore, as CoMSAS uses an exposure threshold, both the FCM surface and the daily food intake have to be correlated with the analytic screening results. Second, highly toxic substances like genotoxicants, mutagenic and reproduction-toxic substancesexcluded in the TTC are covered by the CoMSAS.

Screening for migrants that exceed the exposure threshold of 90 μg/day:
Following migration experiments the presence of as many NIAS’ as possible is elucidated using non-target analytical screening techniques, also known as forest-of-peaks screening. The authors state that there is no single technique available which is able to detect all unknown substances in FCMs. Using coupled approaches, detection of chemicals with unknown origin and a broad variety of chemical and physical properties can be achieved. For the purpose of the presented paper the researchers drew on the following techniques:

Headspace GC-MS for volatile substances.

GC-MS for semi-volatile substances.

Derivatization of non-volatile substances to make these substances more volatile for analysis by GC-MS.

LC-UV/ELSD for non-volatile substances.

Exclusion of the presence of dioxins, heavy metals and other highly toxic or TTC excluded classes of substances:
Substances with known high toxicity should be excluded from FCM in accordance with the TTC. These classes of substances like aflatoxins, organosphosphates and carbamates are denoted in Kroes et al. (2004) and may have lower thresholds specified. For chemicals where insufficient safety information is available the options are either exclusion from FCMs or detailed toxicity evaluation.

Exclusion of potentially genotoxic substances:
For chemicals with genotoxic potential the TTC threshold is set to 0.15 µg/day. Levels above should be avoided unless safety assessment shows acceptable risk due to exposure. Koster and colleagues, however, state that exclusion based on the 28 known structural alerts found in contaminated food simulant with over 100 migrants is challenging. They therefore propose the application of bio assays like AMES, BlueScreen HC assay or assays from the BIOSAFEPAPER project. For the case that in these tests migrant mixtures display genotoxic characteristics, migrants should be separated by chemical and physical properties. Further, each of the fractions should be tested separately to elucidate the harmful chemicals. It is crucial to note here that bioassays are prone to deliver biased results. Due to the low concentration of migrating chemicals, these have first to be enriched and in the following again diluted in appropriate solvents suitable for cell cultures. The types of enrichment columns and the solvents applied yield a range of results and hence impair the sensitivity of the bio assays, therefore possibly leading to false negative results.

Substance specific risk assessment of chemicals exceeding the generic exposure threshold and substances detected in steps 1, 2, and/or 3:
The authors propose that migrants excluded from evaluation by the TTC should be identified and their safety assessed separately if their levels are above the relevant TTC levels, unless the exposure to this substance is below the level mentioned in relevant legislation. For substances with no or negligible risk for human health, safety assessment can continue via CoMSAS. The extent of toxicity testing depends on actual exposure and regulatory boundaries.

Exclusion of allergenic effects based on literature data and/or targeted methods for known allergens:
In the TTC approach proteins are excluded. However, they may be a source of sensitization, which may lead to allergic reactions. Consequently, the authors stress the importance of the evaluation of proteins with known allergenicity as soy, casein, peanut and others, and of novel proteins with the potential of sensitization. However, for most FCM, allergenic effects are not thought to be of relevance.

The authors exemplify in detail the application of the CoMSAS approach in the analysis of three carton samples, of which two are used as FCMs. Results from the CoMSAS showed that no unknown NIAS’ raising health concerns were found in the tested carton samples. For five unknown NIAS’ detected the actual migration would need to be determined to ensure that levels are below the exposure threshold of 90 µg/day. Exceeding the scope of the paper, also known NIAS like mineral oils were found, but the migration and exposure was not further evaluated.

In summary, Koster and colleagues remark that the safety assessment of complex mixtures of known and unknown NIAS’ requires detailed, costly and time-intensive research which might involve animal studies. The introduction of the CoMSAS for the safety assessment of carton may reduce the work load, as for unknown substances present in the migration extract at levels below the exposure limit of 90 µg/day identification of each substance is not considered necessary. For the present analysis of carton FCM samples, this means that instead of identification, quantification and evaluation of 66 to 87 substances for the traditional setting (threshold 10 µg/kg), only 6 to 43 substances had to be analyzed (threshold 90 µg/person/day). Although aiming at the elucidation of complex mixtures, mixture toxicity evaluation is beyond the scope of the CoMSAS approach. The authors understand CoMSAS as a further component in safety assessment focusing on unknown NIAS’.

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